Progress and prospects in anti-HER2 targeted therapy for gastric cancer

<sec><p indent="0mm">Human epidermal growth factor receptor 2 (HER2) was among the earliest molecular targets to be identified and clinically validated in gastric cancer, and it has remained one of the most influential biomarkers guiding therapeutic decision-making in this disease. HER2 status was defined using a binary classification system, categorizing tumors as either HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+ with confirmed fluorescence <italic>in</italic> <italic>situ</italic> hybridization [FISH] amplification) or HER2-negative. The pivotal introduction of trastuzumab in combination with cytotoxic chemotherapy as first-line treatment marked a transformative milestone in the management of advanced HER2-positive gastric cancer, establishing the foundation of HER2-directed therapy and significantly improving clinical outcomes. More recently, advances in the understanding of the gastric cancer immune microenvironment have catalyzed the development of rational combination strategies, while the exploration of novel first-line modalities—including next-generation HER2-directed bispecific antibodies—has become an area of intense clinical investigation. </sec><sec> As trastuzumab is increasingly incorporated into neoadjuvant and perioperative treatment paradigms, new challenges have emerged regarding the optimal sequencing of therapies in the first-line and subsequent treatment settings for HER2-positive disease. In this evolving landscape, it has become clear that the therapeutic relevance of HER2 extends beyond tumors with high-level overexpression or amplification. The advent of antibody–drug conjugate (ADC) technology has fundamentally expanded the spectrum of patients who may benefit from HER2-targeted approaches. In particular, the domestically developed HER2-ADC disitamab vedotin (RC48) has demonstrated clinically meaningful antitumor activity in tumors with low to intermediate HER2 expression, a population historically considered ineligible for HER2-directed therapy. For example, RC48 in combination with the PD-1 inhibitor toripalimab achieved an objective response rate (ORR) of 43% in this subgroup, highlighting the capacity of ADCs to overcome limitations associated with heterogeneous or low-level target expression. In parallel, combination regimens integrating HER2 blockade with anti-angiogenic therapy have shown encouraging results; notably, a triplet regimen comprising trastuzumab, ramucirumab, and paclitaxel reported improvements in both progression-free survival (median PFS <sc>7.1 months)</sc> and overall survival (median OS <sc>13.6 months).</sc> Collectively, these data provided a critical evidentiary basis for the adoption of a refined four-tier HER2 classification system in the 2025 Chinese Society of Clinical Oncology (CSCO) guidelines, thereby broadening eligibility for HER2-directed interventions and facilitating more precise therapeutic stratification. </sec><sec> Although HER2-targeted ADCs are currently approved primarily for use in the second-and third-line settings, their integration into first-line therapy is actively being explored through combinations with immune checkpoint inhibitors, anti-angiogenic agents, and conventional chemotherapy. At the same time, the development of small-molecule HER2-targeted agents, such as pyrotinib, continues to progress, offering alternative mechanisms of HER2 inhibition and additional flexibility in treatment sequencing. As the therapeutic armamentarium rapidly expands, careful attention to safety and tolerability is increasingly important, particularly in light of the distinct toxicity profiles associated with ADCs and multidrug combination regimens. </sec><sec> In conclusion, the treatment paradigm for HER2-positive gastric cancer is undergoing a profound transformation. The transition from a binary HER2 classification framework to a more nuanced stratification system, together with the rapid evolution of HER2-targeted therapies—including ADCs, bispecific antibodies, and innovative combination strategies—is reshaping the practice of precision oncology in gastric cancer. This review systematically summarizes the updated HER2 classification criteria and recent advances in HER2-directed treatment, with the aim of informing optimal clinical decision-making and guiding future research toward improved outcomes across a broader patient population. </sec>